While we previously demonstrated that therapy with cyclophosphamide (CP) was successful as a treatment for Wegener's granulomatosis (WG), drug toxicity has limited its use in certain patients. We have therefore evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Forty-two patients who did not have immediately life-threatening disease were studied. Weekly administration of MTX and prednisone resulted in remission of disease in 33/42 patients (79%). Nineteen of the 34 patients achieving remission experienced a relapse of disease. The estimated median time to relapse for all patients achieving remission was 29 months. Eighty percent of these relapses occurred in patients who had discontinued MTX or had reduced their dose to 15 mg/week or less. Thus, MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. Stenosis of the subglottic trachea (SGS) is a potentially life-threatening complication of WG that requires tracheostomy in up to 50% of cases. We developed a surgical technique for the management of SGS in patients with WG which combines mechanical dilatation of the subglottic trachea with injection of a long-acting glucocorticoid into the stenotic lesion. In 20 patients treated with this technique, none have required tracheostomy and 6 patients with previous tracheostomies were decannulated. Intratracheal dilation-injection therapy provides a safe and effective treatment modality for WG-associated SGS. In preliminary studies we have found that peripheral blood lymphocytes from patients with active WG produce 10-20 fold higher levels of interferon-gamma compared with peripheral blood lymphocytes from normal controls. Increased production of TNF-alpha was also noted, but production of IL-4, IL-5, and IL-10 was not increased. The addition of recombinant IL-10 to cell cultures suppressed the overproduction of interferon-gamma by WG T cells in a dose-dependent manner. These findings have important therapeutic implications since inhibitors of interferon-gamma, TNF-alpha, and other pro-inflammatory cytokines are currently available and may be effective in the treatment of WG and related vasculitic syndromes.